<p>Epigenetic mechanisms, including
DNA methylation, play an important role in regulation of stem cell fate and
tumorigenesis. The Ten-Eleven-Translocation 2 (TET2) is a core enzyme for DNA
demethylation by catalyzing the conversion of 5-methylcytosine (5mC) to
5-hydromethylcytosine (5hmC). It has been shown that TET2 is the main regulator
of hematopoietic stem cell homeostasis and loss of TET2 is highly associated
with hematopoietic malignancies. Our previous work has also shown that loss of
TET2 expression is linked to promotion of an epithelial-mesenchymal-transition phenotype
and expansion of a breast cancer stem cell-like population with skewed
asymmetric cell division in vitro;
however, the in vivo role that
TET2 plays in regulation of mammary stem cell (MaSC) fate and development of
mammary pathology has yet to be determined. Here, using our newly established
mammary-specific Tet2-knockout mouse model, the data reveals for the first time
that TET2 plays a pivotal role in mammary gland development via directing MaSC
to luminal lineage commitment in vivo. Furthermore, we find that TET2
coordinates with FOXP1 to target and demethylate FOXA1, GATA3, and ESR1, key
transcription factors that orchestrate mammary luminal lineage specification
and endocrine response and are often silenced by DNA methylation in aggressive
human breast cancers. Finally, loss of TET2 expression leads to promotion of
mammary tumor development with defective luminal cell differentiation and tamoxifen
resistance in a PyMT;Tet2 deletion breast cancer mouse model. As a result, this study provides a previously
unidentified role for TET2 in governing luminal lineage specification and
endocrine response that underlies resistance to anti-estrogen treatments.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/11303504 |
| Date | 03 December 2019 |
| Creators | Mi Ran Kim (8066174) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/ROLE_OF_TET2_IN_LUMINAL_DIFFERENTIATION_AND_HORMONE_THERAPY_RESPONSE_IN_BREAST_CANCER/11303504 |
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